The present invention relates to novel cyclosporin analogs and methods of treatment for the prevention of organ transplantation rejection and the treatment of autoimmune diseases in a subject. The present invention further relates to pharmaceutical compositions comprising the compounds of the present invention and processes for their production.
The cyclosporins comprise a class of structurally distinctive, cyclic, poly-N-methylated undecapeptides, commonly possessing pharmacological activity, in particular immunosuppressive, anti-inflammatory or anti-parasitic activity. The first of the cyclosporins to be isolated was the naturally occurring fungal metabolite cyclosporin, Cyclosporin A represented as follows: 
Since the original discovery of cyclosporin, a wide variety of naturally occurring cyclosporins have been isolated and identified, and many further non-natural cyclosporins have been prepared by total- or semi-synthetic means or by the application of modified culture techniques. The class comprising cyclosporins is thus now substantial and includes, for example, the naturally occurring Cyclosporins A through Z, for example, [Thr]2, [Val]2, [Nva]2 and [Nva]2xe2x88x92, [Nva]5-Cyclosporin (also known as Cyclosporins C, D, G and M respectively), [(D)MeVal]11-Cyclosporin (also known as Cyclosporin H), [cf., Traber et al.;1, Helv. Chim. Acta, 60, 1247-1255 (1977); Traber et al.; 2, Helv. Chim. Acta, 65, 1655-1667 (1982); Kobel et al.; Europ. J. Applied Microbiology and Biotechnology, 14, 273-240 1982); and Von Wartburg et al.; Progress in Allergy, 38, 28-45, 1986)]; as well as various non-natural cyclosporin derivatives and artificial or synthetic cyclosporin derivatives and artificial or synthetic cyclosporins including dihydrocyclosporins [in which the MeBmt-residue is saturated by hydrogenation]; derivatized cyclosporins (e.g., in which the 3xe2x80x2-O-atom of the MeBmt-residue is acylated or a further substituent is introduced at the xcex1-carbon atom of the sarcosyl residue at the 3-position); and cyclosporins in which variant amino acids are incorporated at specific positions within the peptide sequence, for example, [3-O-acetyl-MeBmt]1-Cyclosporin (also known as Dihydro-cyclosporin D), [(D)Ser]8-Cyclosporin, [Melle]11-Cyclosporin, [MeAla]6-Cyclosporin, [(D) Pro]3-Cyclosporin etc., employing the total synthetic method for the production of cyclosporins developed by R. Wengerxe2x80x94see e.g. Traber et al., 1; Traber et al., 2; and Kobel et al., loc cit. U.S. Pat. Nos. 4,108,985, 4,220,641, 4,288,431, 4,554,351, 4,396,542 and 4,798,823; European Patent Publication Nos. 34,567A, 56,782A, 300,784A and 300,785; International Patent Publication No. WO 86/02080 and UK Patent Publication Nos. 2,206,119 and 2,207,678; Wenger 1, Transpl. Proc., 15 Suppl. 1:2230 (1983); Wenger 2, Angew. Chem. Int. Ed. 24 77 (1985) and Wenger 3, Progress in the Chemistry of Organic Natural Products, 50, 123 (1986).
The compound Cyclosporin A has found wide use since its introduction in the fields of organ transplantation and immunomodulation, and has brought about a significant increase in the success rate for transplantation procedures. Undesired side effects associated with cyclosporin, such as nephrotoxicity, have led to a continued search for immunosuppressant compounds having improved, efficacy and safety.
The present invention relates to novel cyclosporin analogs and methods of treatment for the prevention of organ transplantation rejection and the treatment of autoimmune diseases in a subject. The present invention further relates to pharmaceutical compositions comprising the compounds of the present invention and processes for their production.
More particularly, the present invention relates to a cyclosporin analog of the following formula (I) or a pro-drug or pharmaceutically acceptable salt thereof: 
In particular, residue A may be represented by either formula A1 or A2 as illustrated below: 
where X is absent, xe2x80x94C1-C6-alkyl- or xe2x80x94C3-C6-cycloalkyl-; Y is selected from the groups: aryl, substituted aryl, heteroaryl, and substituted heteroaryl; residue B is -xcex1Abu-, -Val-, -Thr- or -Nva-; and residue U is -(D)Ala-, -(D)Ser-, xe2x80x94[O-(2-hydroxyethyl)(D)Ser]-, xe2x80x94[O-acyl(D)Ser]- or xe2x80x94[O-(2-acryloxyethyl)(D)Ser]-.
In a second embodiment, the present invention relates to the use of the cyclosporin analogs of the present invention or a pro-drug or pharmaceutically acceptable salt thereof in pharmaceutical compositions for the treatment of autoimmune diseases or for the prevention of organ transplantation rejection in a subject.
In a third embodiment, the present invention relates to processes for the production of novel cyclosporin analogs of the present invention. In a preferred embodiment, the present invention relates to the processes for the production of cyclosporin analogs of formula I, where residue A may be represented by either formula A1 or A2.
The present invention also contemplates method(s) of treatment of autoimmune diseases or prevention of organ transplant rejection in a subject by administering to the subject therapeutically effective amounts of the cyclosporin analogs of the present invention with or without the concurrent use of other drugs or pharmaceutically acceptable carriers or excipients.